Analogues of N-benzyloxydihydrotriazines: in vitro antimalarial activity against Plasmodium falciparum

The potency of antimalarial dihydrofolate reductase inhibitors, alone and in synergistic combination with dihydropteroate synthetase inhibitors, against the Kenyan K39 strain of Plasmodium falciparum (pyrimethamine resistant) and against normal replicating human bone marrow cells in in vitro culture has been studied. Therapeutic indices and rank order of synergistic potency were derived. Trimethoprim, pyrimethamine, and the quinazolines WR159412 and WR158122 had the smallest therapeutic indices (1.39, 4.38, 2.56, and 90.0, respectively), while the three triazines clociguanil, WR99210, and chlorcycloguanil had the largest (3,562, 3,000, and 2,000, respectively). In rank order of decreasing activity against P. falciparum, the six most potent drug combinations were WR99210-dapsone, chlorcycloguanil-dapsone, WR158122-dapsone, WR159412-dapsone, WR159412-sulfamethoxazole, and chlorcycloguanil-sulfamethoxazole; pyrimethaminesulfadoxine was the least potent combination. These experiments form a basis for the selection of rapidly eliminated antifolate combinations for further clinical testing.

Section: Discussionsupporting

confidence: 91%

In vitro activities of novel antifolate drug combinations against Plasmodium falciparum and human granulocyte CFUs

Winstanley

Mberu

Szwandt

et al. 1995

“…A stock solution of WR99210, utilized in vitro, was initially dissolved in 100% dimethyl sulfoxide (DMSO) and then diluted in complete tissue culture medium (IMDM-C) (Iscove's modified Dulbecco's medium with NaHCO 3 [Gibco]). Working concentrations of WR99210 were made using IMDM-C.…”

Section: Infection Of Micementioning

confidence: 99%

Triazine Inhibits Toxoplasma gondii Tachyzoites In Vitro and In Vivo

Mui

Jacobus²,

Milhous

et al. 2005

The dihydrofolate reductase (DHFR) domain of the bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) molecule is one of the molecular targets for gold standard treatments for diseases caused by Plasmodium falciparum and Toxoplasma gondii. Those compounds that have demonstrated inhibition of P. falciparum and/or T. gondii DHFR-TS in vitro and in vivo include pyrimethamine, cycloguanil, and trimethoprim. Rapid development of resistance of malaria parasites to pyrimethamine or cycloguanil led to the development of WR99210, which demonstrated no cross-resistance to other antifolates. The triazine WR99210 [4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(2,4,5-trichlorophenoxypropyloxy)-1,3,5-triazine] (Fig. 1A) has been found to be a tight-binding and potent inhibitor of P. falciparum DHFR-TS (2-4, 9-11), with activity 2 logs greater than that of pyrimethamine. It is also active against P. vivax (5, 6, and

“…Most of the work was done with clone NC-1 (43) of the FCB strain. FCB is a Colombian strain and is chloroquine resistant and pyrimethamine susceptible (10). Some studies used clone HB-3 of the Honduras I/CDC strain.…”

mentioning

confidence: 99%

In vitro susceptibilities of Plasmodium falciparum to compounds which inhibit nucleotide metabolism

Queen

Jagt

Reyes

1990

A unique metabolic feature of malaria parasites is their restricted ability to synthesize nucleotides. These parasites are unable to synthesize the purine ring and must therefore obtain preformed purine bases and nucleosides from the host cell, the erythrocyte. On the other hand, pyrimidines must be synthesized de novo because of the inability of the parasites to salvage preformed pyrimidines. Thus, one would anticipate that the blockage of purine salvage or pyrimidine de novo synthesis should adversely affect parasite growth. This premise was tested in vitro with a total of 64 compounds, mostly purine and pyrimidine analogs, known to inhibit one or more steps of nucleotide synthesis. Of the 64 compounds, 22 produced a 50% inhibition of the growth of the human malaria parasite Plasmodium falkiparum at a concentration of 50 ,uM or less. Inhibition of the growth of chloroquine-resistant clones ofP. fakciparum did not differ significantly from that of the growth of chloroquine-susceptible clones. Two of the compounds which effectively inhibited parasite growth, 6-mercaptopurine and 6-thioguanine, were found to be potent competitive inhibitors of a key purine-salvaging enzyme (hypoxanthine-guanine-xanthine phosphoribosyltransferase) of the parasite.The worldwide resurgence of human malaria during the past decade (60) has been due in part to the rapid spread of Plasmodium falciparum strains resistant to chloroquine and other commonly used antimalarial drugs (21, 41). In view of this resurgence, there is currently an urgent need to develop and identify additional safe and effective drugs (47).A rational approach to drug development is to identify drugs which can be directed at unique metabolic targets in the parasite. One such target is the synthesis of purine and pyrimidine nucleotides. Unlike humans, malaria parasites cannot make purines de novo and must therefore obtain purine bases and nucleosides from the erythrocyte host cell and then metabolize these to nucleotides by salvage pathways (54). Another metabolic distinction between these parasites and humans is that P. falciparum relies exclusively on pyrimidine synthesis de novo because of its inability to salvage preformed pyrimidines (54). Thus, drugs capable of blocking either purine salvage or pyrimidine de novo synthesis would be expected to show strong antimalarial activity.In the present study, we measured the in vitro antimalarial activity of 64 compounds known to inhibit one or more aspects of nucleotide or nucleic acid metabolism. A number of these compounds were also tested for their ability to inhibit a key purine-salvaging enzyme (43)